Melanoma is the most aggressive form of skin cancer and is an increasing health problem around the world, with incidence rates on the rise year on year. Once melanoma has metastasised there are few effective treatments, and mortality is high. Melanoma is capable of rapid metastasis and is often refractory to conventional chemotherapy and radiotherapy. This resistance is a major obstacle to improving patient survival and with the paucity of effective therapeutic agents, there exists a need to develop novel, therapeutically effective approaches to treat melanoma.
Increased understanding of the molecular biology of melanoma, including the identification of gene mutations as potential drug targets and of specific signaling pathways activated in melanoma, such as the insulin like growth factor 1 receptor (IGF1R) pathway, offers hope for the development of improved therapies. IGF1R is overexpressed in malignant melanoma compared to benign naevi and mediates processes such as survival, proliferation and motility. IGF1R stimulation leads to activation of two main downstream signaling pathways: the PI3K-Akt-TOR pathway and the Ras-Raf-MEK-ERK pathway, both of which are important for melanoma pathogenesis. Mutations occur in critical molecules of these pathways including NRAS (9-15% of melanomas), BRAF (66% of melanomas) and PTEN (30-60% of melanomas), resulting in constitutive activation of the pathways, promoting cell proliferation, survival, migration and invasion. While recent clinical trials with the mutant BRAF inhibitor PLX4032 (RG7204/Vemurafenib/Zelboraf®) have produced dramatic shrinkage of metastatic melanoma tumours, virtually all patients develop resistance. Importantly, upregulation of IGF1R signaling is a mechanism of ERK-independent resistance to BRAF inhibition. Thus, IGF1R and its downstream signaling pathways are potential targets for cancer therapy.
MicroRNAs (miRNAs) are a class of highly conserved, small (typically 21-25 nucleotides) non-coding RNAs that regulate both mRNA degradation and translation, at least partially through their ability to bind to the 3′-UTR of target genes via a ‘seed region’ of the miRNA. miRNAs are generated from RNA precursors (pri-miRNAs) that usually contain several hundred nucleotides transcribed from regions of non-coding DNA. Pri-miRNAs are processed in the nucleus by RNase III endonuclease to form stem-loop precursors (pre-miRNAs) of approximately 70 nucleotides. Pre-miRNAs are actively transported into the cytoplasm where they are further processed into short RNA duplexes, typically of 21-23 nucleotides. The functional miRNA strand dissociates from its complementary non-functional strand and locates within, the RNA-induced-silencing-complex (RISC). (Alternatively, RISC can directly load pre-miRNA hairpin structures.) miRNAs bind the 3′UTRs of target mRNAs and important in this binding is a ‘seed region’ of approximately 6-7 nucleotides near the 5′ end of the miRNA (typically nucleotide positions 2 to 8). miRNA-induced regulation of gene expression is typically achieved by translational repression, either degrading proteins as they emerge from ribosomes or ‘freezing’ ribosomes, and/or promoting the movement of target mRNAs into sites of RNA destruction.
miRNAs are crucial to many normal cellular functions and are involved in processes such as stem cell division, embryonic development, cellular differentiation, inflammation and immunity. Increasingly, specific miRNAs, and expression patterns and altered regulation of expression of individual miRNAs, are also being implicated in a variety of disease conditions, including cancer. miR-7-5p is characterized as a tumour suppressor miRNA in several cancer types, where it targets and represses molecules such as IGF1R (insulin like growth factor 1 receptor), PAK1 (p21-activated kinase 1), IRS-1/2 (insulin receptor substrates 1 and 2), EGFR (epidermal growth factor receptor), FAK (focal adhesion kinase) and RAF1 (v-raf-1 murine leukaemia viral oncogene homologue 1).